Ulcerative colitis (UC) is an idiopathic, chronic relapsing and remitting, non-specific inflammatory disease of the colonic mucosa. Acute episodes are characterized by chronic diarrhea, rectal bleeding and abdominal pain. Stool volume correlates directly with disease severity, since the colon becomes increasingly unable to reabsorb water and electrolytes as inflammation of the mucosa increases. Loss of water and electrolytes can lead to dehydration, weight loss and serum electrolyte disturbances. Inflammation of the mucosa leads to erosions, which eventually result in rectal bleeding. Anemia and hypoalbuminemia often develop as the disease progresses. Muscosal Inflammation also leads to smooth muscle spasm that, in turn, causes urgency to defecate and tenesmus. Systemic manifestations include anorexia, weight loss, fatigue, fever, increased sedimentation rate, arthritis, eye inflammation, anxiety, tachycardia, and elevation in liver function tests (LFTs).
UC also has a profound emotional and social impact on the affected individual. The etiology and pathogenesis of UC are multifactorial and incompletely understood. One theory is that the disease results from inappropriate activation of the mucosal immune system, resulting in the inflammatory response. Theories regarding the inappropriate activation suggest a role for genetic predisposition and/or environment triggers.
UC is most commonly reported in Northern Europe and the United States; reported less frequently in the Middle East and the Southern Hemisphere; and infrequently seen in South America, Asia and Africa. The annual incidence rate is 10.4 to 12.0 cases per 100,000 people with a prevalence rate of 35 to 100 cases per 100,000 people. Although UC occurs at any age, the incidence peaks at 15 to 25 years and 55 to 65 years. The disease is 30% more predominant in females; and a higher incidence is associated with the Jewish population. The goal of treatment in UC is to induce and maintain remission, and improve quality of life.
Subjects with ulcerative colitis may experience periods of remission (times when the symptoms go away) that can last for months or years. However, most subjects' symptoms eventually return. Active therapy is treatment given to treat UC symptoms when they are active. Maintenance therapy refers to treatment given to subjects to enable them to stay in remission, to maintain their health in a disease-free, or limited-disease, state. Maintenance medications must be taken for a prolonged period of time.
The clinical efficacy of oral mesalamine compounds to treat UC has related to delivery of the intact molecule to the colonic mucosa without breakdown during digestion. Currently, oral mesalamine treatments are based on 3 types of delivery systems: (1) azo-bonded to release drug in the colon once the drug is exposed to colonic bacteria (Azulfidine, Dipentum® capsules (olsalazine), and balsalazide; (2) polymer coated (Asacol® mesalamine) delayed-release tablets) to provide a release of drug when the pH in the digestive tract reaches the desired value; and (3) time-dependent release mechanisms (Pentasa® capsules). Problems with other formulations include variation within formulations in the release of mesalamine, including premature release, the possibility of dose dumping, and sensitivity to conditions that increase gastric pH and cause premature release of mesalamine (e.g., ingestion of a meal).
Examples of mesalamine formulations may be found in U.S. Pat. Nos. 6,277,412; 6,551,620 and US Publication 2003/0133983.
Many subject's suffering from bowel diseases (BD), such as ulcerative colitis, diverticulitis, Crohn' s disease, and inflammatory bowel disease are not adequately controlled on currently available formulations of available medications.